Proteomic risk score for osteoarthritis (OA)

Abstract

This specification presents a method for determining the risk of developing osteoarthritis (OA) and / or progressing to total joint replacement (TJR) in subjects by determining an OA proteomics risk score for those subjects, as well as a method for determining the treatment response to NGF antagonist or NSAID treatment.

Description

Technical Field

[0001] The present disclosure relates to a method for determining the risk of developing osteoarthritis (OA) and / or the risk of progressing to total joint replacement (TJR) in a subject by determining an OA proteomic risk score for the subject, and a method for determining a treatment response to a nerve growth factor (NGF) antagonist or a non-steroidal anti-inflammatory drug (NSAID).

Background Art

[0002] A proteomic risk score combines information on the protein expression levels or circulating levels of a number of proteins derived from disease-related studies to create a single quantitative measure for each individual. A proteomic risk score is typically constructed as a weighted sum of the expression levels or circulating levels of a selected group of proteins from subjects with a particular disease, compared to a reference population. The resulting score is approximately normally distributed in the general population, and the higher the score, the higher the risk or disease, and / or the need for a particular therapeutic treatment regimen. With the increasing availability of proteomic data in large-scale cohort studies, the incorporation of proteomic risk scores may become more widespread. Although this previously required expertise, it has become more feasible to calculate scores for use in analysis as tools and data availability improve.

[0003] Osteoarthritis is the most common form of arthritis, affecting an estimated 303 million people worldwide in 2017, with pain being the primary symptom associated with the disease. OA is a degenerative disease of the synovial joints, including those of the knees, hips, facet joints of the spine, and hands. Risk factors for OA include age, a history of joint injury, obesity, female gender, and genetics. These risk factors are related to the underlying pathogenesis of OA, a complex process influenced by biomechanical changes, chronic low-level inflammation, and aging. All of these processes can accelerate the breakdown and remodeling of joint tissue, ultimately leading to a breakdown of the structural integrity of the joint. While these arthritis and osteoarthritis do not directly lead to death, they cause pain and limb dysfunction as cartilage and bone destruction progresses over time, significantly impacting daily life.

[0004] R475-OA-1688 is a phase 3 randomized, double-blind, multidose, placebo- and NSAID-controlled trial to evaluate the efficacy and safety of facinumab in patients with pain due to osteoarthritis of the knee or hip. The primary efficacy objective of R475-OA-1688 is to evaluate changes in the Western Ontario and McMaster Osteoarthritis (WOMAC) pain subscale and functional subscale from baseline to 24 weeks in patients treated with facinumab compared with patients treated with NSAIDs or placebo. The primary safety objective of R475-OA-1688 is to evaluate the incidence of total arthroplasty during the treatment and follow-up periods. [Overview of the project]

[0005] This disclosure provides a method for determining the risk of developing osteoarthritis (OA) in a subject, the method comprising determining or determining a proteomic risk score for the subject, the proteomic risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the proteomic risk score for the subject is greater than or equal to a threshold proteomic risk score, the subject has an increased risk of developing OA, and if the proteomic risk score for the subject is less than a threshold proteomic risk score, the subject has a reduced risk of developing OA.

[0006] The disclosure also provides a method for determining the risk of progression to total joint replacement (TJR) of a subject, the method comprising determining or having determined an osteoarthritis proteomics risk score of the subject, the osteoarthritis proteomics risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the subject's osteoarthritis proteomics risk score is greater than or equal to the threshold osteoarthritis proteomics risk score, the subject has an increased risk of progression to TJR, and if the subject's osteoarthritis proteomics risk score is less than the threshold osteoarthritis proteomics risk score, the subject has a decreased risk of progression to TJR.

[0007] The disclosure also provides a method for determining the treatment response of a subject treated with an NGF antagonist, the method comprising determining or determining the osteoarthritis proteomics risk score of the subject, the osteoarthritis proteomics risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the subject's osteoarthritis proteomics risk score is greater than or equal to the threshold osteoarthritis proteomics risk score, the subject has a low response to the NGF antagonist, and if the subject's osteoarthritis proteomics risk score is less than the threshold osteoarthritis proteomics risk score, the subject has an increased response to the NGF antagonist.

[0008] The disclosure also provides a method for determining the treatment response of a subject treated with an NSAID, the method comprising determining or determining a proteoarthritis risk score for the subject, the proteoarthritis risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the proteoarthritis risk score for the subject is greater than or equal to the threshold proteoarthritis risk score, the subject has a reduced response to the NSAID, and if the proteoarthritis risk score for the subject is less than the threshold proteoarthritis risk score, the subject has an increased response to the NSAID.

[0009] The disclosure also provides a method for determining a treatment response in a subject, the method comprising determining or determining a subject's osteoarthritis proteomics risk score, the osteoarthritis proteomics risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the subject's osteoarthritis proteomics risk score is greater than or equal to a threshold osteoarthritis proteomics risk score, the subject has a low treatment response, and if the subject's osteoarthritis proteomics risk score is less than a threshold osteoarthritis proteomics risk score, the subject has an increased treatment response.

[0010] This patent or application document includes at least one drawing drawn in color. Copies of this patent or patent application publication, including the color drawing(s), will be provided by the Patent Office upon request and payment of the necessary fees. [Brief explanation of the drawing]

[0011] [Figure 1] This graph shows the proportion of total joint replacement surgery in OA patients in the UK Biobank Pharma Proteomics Project (UKBPPP), stratified by proteomics risk score quartiles (X-axis) (Y-axis). Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. OR per SD = odds ratio per standard deviation, N samples = number of subjects in the study, N = number of subjects in each quartile. [Figure 2] This shows Kaplan-Meier curves for total arthroplasty in OA patients from the UK Biobank Pharma Proteomics Project (UKB PPP), stratified by proteomics risk score quartiles. Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. [Figure 3]This graph shows the proportion of total arthroplasty (Y-axis) in all patients with osteoarthritis (OA) in the R475-OA-1688 clinical trial (including all patients treated with facinumab, NSAIDs, or placebo), stratified by proteomics risk score quartile (X-axis). Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. OR = odds ratio per standard deviation, N samples = number of subjects in the study, N = number of subjects in each quartile. [Figure 4] This graph shows the proportion of total arthroplasty (Y-axis) in OA patients treated with all facinumab doses (including all 1q4w, 3q4w, and 6q8w) in the R475-OA-1688 clinical trial, stratified by proteomics risk score quartile (X-axis). Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. OR = odds ratio per standard deviation, N samples = number of subjects in the study, N = number of subjects in each quartile. [Figure 5] This graph shows the proportion of total arthroplasty (Y-axis) in OA patients treated with high-dose facinumab (including both 3q4w and 6q8w) in the R475-OA-1688 clinical trial, stratified by proteomics risk score quartile (X-axis). Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. OR = odds ratio per standard deviation, N samples = number of subjects in the study, N = number of subjects in each quartile. [Figure 6] This graph shows the proportion of total arthroplasty (OA) patients treated with facinumab 1q4w in the R475-OA-1688 clinical trial, stratified by proteomics risk score quartile (X-axis) (Y-axis). Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. OR = odds ratio per standard deviation, N samples = number of subjects in the study, N = number of subjects in each quartile. [Figure 7]This graph shows the proportion of total arthroplasty (RO) among NSAID-treated patients in the R475-OA-1688 clinical trial, stratified by proteomics risk score quartiles (X-axis) (Y-axis). Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. OR = odds ratio per standard deviation, N samples = number of subjects in the study, N = number of subjects in each quartile. [Figure 8] This graph shows the proportion of total arthroplasty (OA) patients treated with placebo in the R475-OA-1688 clinical trial, stratified by proteomics risk score quartiles (X-axis) (Y-axis). Quartile 4 represents the highest risk, and quartile 1 represents the lowest risk. OR = odds ratio per standard deviation, N samples = number of subjects in the study, N = number of subjects in each quartile. [Figure 9] This graph shows the least squares mean change (Y axis) of WOMAC pain score from baseline over time (X axis) in all patients treated with facinumab 1q4w, NSAIDs, and placebo, stratified by proteomics risk score risk group. The high-risk group is defined as patients in the 4th OA PRS quartile, while patients in the 1st to 3rd quartiles are defined as the low-risk group. [Figure 10] This graph shows the least squares mean change (Y-axis) of WOMAC function score from baseline over time (X-axis) in all patients treated with facinumab 1q4w, NSAIDs, and placebo, stratified by proteomics risk score risk group. The high-risk group is defined as patients in the 4th OA PRS quartile, while patients in the 1st to 3rd quartiles are defined as the low-risk group. [Figure 11] The graph shows the least squares mean change (Y axis) of WOMAC pain score from baseline over time (X axis) in all patients treated with facinumab 1q4w, celecoxib, diclofenac, and placebo, stratified by proteomics risk score risk group. The high-risk group is defined as patients in the 4th OA PRS quartile, while patients in the 1st to 3rd quartiles are defined as the low-risk group. [Figure 12]The graph shows the least squares mean change (Y axis) of WOMAC function score from baseline over time (X axis) in all patients treated with facinumab 1q4w, celecoxib, diclofenac, and placebo, stratified by proteomics risk score risk group. The high-risk group is defined as patients in the 4th OA PRS quartile, while patients in the 1st to 3rd quartiles are defined as the low-risk group. [Modes for carrying out the invention]

[0012] Protein expression or circulating levels may play a significant role in the risk of developing a disease and may potentially influence how such a disease or condition progresses to more advanced stages requiring specific interventions. A proteomics risk score combines information from multiple protein expression or circulating levels derived from disease-related studies to create a single, composite quantitative measure that reflects each individual's disease risk. Combining risk assessments of multiple proteins offers the advantage of improved predictive power. Individuals with higher expression or circulating levels of proteins associated with a particular disease will have a higher proteomics risk score than individuals with lower expression or circulating levels of the same disease-related proteins. Risk can be assessed at several thresholds, for example, in units of percentiles, standard deviations of the population distribution, or absolute values. This disclosure relates to an unexpected finding that, in general, stratification of subjects by OA proteomics risk score is useful in identifying subjects at high risk of developing OA and / or subjects at high risk of avoiding arthropathy side effects of NGF antagonists in the treatment of OA pain, and is also useful in demonstrating differential responses to both NGF antagonists and NSAID treatments.

[0013] Various terms relating to aspects of this disclosure are used throughout this specification and the claims. Unless otherwise indicated, such terms shall be given their ordinary meanings in the art. Other terms specifically defined shall be construed in accordance with the definitions set forth herein.

[0014] Unless otherwise expressly provided, none of the methods or embodiments described herein are intended to be construed as requiring the steps to be performed in a specific order. Therefore, unless the method claims specifically specify in the claims or description that the steps should be limited to a particular order, they are not intended to be construed as requiring such order in any respect. This also applies to all possible implicit criteria of interpretation, including logical matters relating to the arrangement of a process or workflow, general meanings arising from grammatical structure or punctuation, or the number or types of embodiments described herein.

[0015] As used herein, the singular forms "a," "an," and "the" encompass multiple referents unless otherwise clearly indicated by the context. Where used herein, the term “about” means that the listed figures are approximations and small variations will not significantly affect the practice of the disclosed embodiments. Where figures are used, unless otherwise indicated by the context, the term “about” means that the figures may vary by ±10% and remain within the scope of the disclosed embodiments.

[0016] As used herein, the term “antagonist” means that a given compound is capable of inhibiting the activity of a particular protein or other substance within a cell to at least a certain extent. This can be achieved by a direct interaction of the compound with a given protein or substance ("direct inhibition") or by an interaction of the compound with other proteins or substances inside or outside the cell, which leads to at least partial inhibition of the activity of the protein or substance ("indirect inhibition"). Inhibition of protein activity can also be achieved by suppressing the expression of the target protein. Techniques for inhibiting protein expression include, but are not limited to, antisense inhibition, siRNA-mediated inhibition, miRNA-mediated inhibition, ribozyme-mediated inhibition, DNA-directed RNA interference (DdRNAi), RNA-directed DNA methylation, activator-like effector nuclease (TALEN)-mediated inhibition, zinc finger nuclease-mediated inhibition, aptamer-mediated inhibition, and CRISPR-mediated inhibition.

[0017] As used herein, the terms “nerve growth factor” and “NGF” refer to nerve growth factor and its variants that retain at least some of the activity of NGF (including, for example, splice variants and protein processing variants). As used herein, NGF includes all mammalian species of naturally occurring sequence NGF, including humans, non-human primates, dogs, cats, horses, or cattle.

[0018] The term "NGF antagonist" refers to any molecule that blocks, inhibits, or reduces (significantly) NGF biological activity, including downstream pathways mediated by NGF signaling, such as receptor binding and / or induction of cellular responses to NGF. The term "antagonist" does not imply any specific mechanism of biological action, but is considered to expressly include and encompass all possible pharmacological, physiological, and biochemical interactions with NGF, whether direct or indirect, or whether they interact via NGF, its receptors, or other mechanisms, and the results that may be achieved by a variety of different, chemically diverse compositions. Exemplary NGF antagonists include, but are not limited to, anti-NGF antibodies, antisense molecules directed to NGF (including antisense molecules directed to nucleic acids encoding NGF), NGF antagonist compounds, NGF structural analogs, dominant-negative mutations of the TrkA receptor that binds to NGF, TrkA immunoadhesins, anti-TrkA antibodies, anti-p75 antibodies, antisense molecules directed to either or both of the TrkA and / or p75 receptors (including antisense molecules directed to nucleic acid molecules encoding TrkA or p75), and kinase inhibitors. For the purposes of this disclosure, the term “antagonist” should be understood to encompass all previously identified terms, names, and functional states and properties in which NGF itself, NGF biological activity (including, but not limited to, the ability to mediate any aspect of pain), or the consequences of biological activity are substantially inactivated, reduced, or neutralized to any significant degree. In some embodiments, an NGF antagonist binds to (physically interacts with) NGF (e.g., an antibody), binds to an NGF receptor (such as a TrkA receptor or p75 receptor), reduces (interferes with and / or blocks) downstream NGF receptor signaling, and / or inhibits (reduces) NGF synthesis, production, or release.In other embodiments, the NGF antagonist binds to NGF and prevents dimerization of the TrkA receptor and / or autophosphorylation of TrkA. In other embodiments, the NGF antagonist inhibits or reduces NGF synthesis and / or production (release). Examples of types of NGF antagonists are provided herein.

[0019] As used herein, the term "NSAID" refers to any non-steroidal anti-inflammatory drug that includes, but is not limited to, any of the NSAIDs disclosed herein.

[0020] As used herein, "preventive treatment" and "prevention" refer to administration to a subject who does not currently have OA and has never had OA. As used herein, the term "subject" encompasses any animal, including mammals. Mammals include, but are not limited to, livestock (e.g., horses, cows, pigs), pets (e.g., dogs, cats), laboratory animals (e.g., mice, rats, rabbits), and non-human primates (e.g., apes and monkeys). In some embodiments, the subject is a human. In some embodiments, the subject is a patient under the care of a physician.

[0021] As used herein, "therapeutic treatment" refers to administering a therapeutic agent to a subject having OA. As used herein, the terms "treat", "treatment", or "treating" refer to administering a therapeutic agent for prophylactic and / or therapeutic purposes.

[0022] This disclosure provides a method for determining the risk of a subject developing osteoarthritis (OA). The method includes determining or having determined an osteoarthritis proteomics risk score for the subject, the osteoarthritis proteomics risk score including a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA. If the subject's osteoarthritis proteomics risk score is greater than or equal to the threshold osteoarthritis proteomics risk score, the subject has an increased risk of developing OA. If the subject's osteoarthritis proteomics risk score is less than the threshold osteoarthritis proteomics risk score, the subject has a decreased risk of developing OA.

[0023] This disclosure also provides a method for determining the risk of a subject progressing to total joint replacement (TJR). The method includes determining or having determined an osteoarthritis proteomics risk score for the subject, the osteoarthritis proteomics risk score including a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA. If the subject's osteoarthritis proteomics risk score is greater than or equal to the threshold osteoarthritis proteomics risk score, the subject has an increased risk of progressing to TJR. If the subject's osteoarthritis proteomics risk score is less than the threshold osteoarthritis proteomics risk score, the subject has a decreased risk of progressing to TJR.

[0024] The disclosure also provides a method for determining the treatment response of a subject treated with an NGF antagonist, the method comprising determining or determining the osteoarthritis proteomics risk score of the subject, the osteoarthritis proteomics risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the subject's osteoarthritis proteomics risk score is greater than or equal to the threshold osteoarthritis proteomics risk score, the subject has a low response to the NGF antagonist, and if the subject's osteoarthritis proteomics risk score is less than the threshold osteoarthritis proteomics risk score, the subject has an increased response to the NGF antagonist.

[0025] The disclosure also provides a method for determining the treatment response of a subject treated with an NSAID, the method comprising determining or determining a proteoarthritis risk score for the subject, the proteoarthritis risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the proteoarthritis risk score for the subject is greater than or equal to the threshold proteoarthritis risk score, the subject has a reduced response to the NSAID, and if the proteoarthritis risk score for the subject is less than the threshold proteoarthritis risk score, the subject has an increased response to the NSAID.

[0026] The disclosure also provides a method for determining a treatment response in a subject, the method comprising determining or determining a subject's osteoarthritis proteomics risk score, the osteoarthritis proteomics risk score comprising a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA, wherein if the subject's osteoarthritis proteomics risk score is greater than or equal to a threshold osteoarthritis proteomics risk score, the subject has a low treatment response, and if the subject's osteoarthritis proteomics risk score is less than a threshold osteoarthritis proteomics risk score, the subject has an increased treatment response.

[0027] In some embodiments, subjects may have had OA within the past 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months. In some embodiments, subjects may have had OA within the past 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years. Subjects may include subjects who have been hospitalized for OA-related symptoms, and subjects who are currently hospitalized.

[0028] The osteoarthritis proteomics risk score includes a weighted aggregate of the expression or circulating levels of one or more proteins associated with OA. The number of proteins associated with OA may be one protein, at least about two proteins, at least about five proteins, at least about ten proteins, at least about fifteen proteins, at least about twenty proteins, at least about thirty proteins, at least about forty proteins, at least about fifteen proteins, at least about 100 proteins, or at least about 200 proteins.

[0029] Table 1 shows the association analysis of the top 199 proteins that were statistically significant after Bonferroni correction with the overall protein association data (p-value cutoff: 1.7e-5).

[0030] Table 1-1

[0031] Table 1-2

[0032] Table 1-3

[0033] Table 1-4

[0034] Table 1-5

[0035] Table 1-6

[0036] In some embodiments, one or more proteins associated with OA include collagen alpha-1(IX) chain (COL9A1), cartilage acid protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrine-3 (MATN3), cartilage oligomeric substrate protein (COMP), and CU. Protein B-domain 1 (CDCP1), Protein BRICK1 (BRK1), Gastrin (GAST), Collagen alpha-3 (VI) chain (COL6A3), Protein AMBP (AMBP), Protein V-set and immunoglobulin domain 2 (VSIG2), Fibroblast growth factor binding protein 2 (FGFBP2), Annexin A10 (ANXA10), Chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain 4 (TIMD4), Osteopontin (SP P1), protein delta homolog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor-binding protein 4 (IGFBP4), fatty acid-binding protein, heart (FABP3), trigger receptor 2 (TREM2) expressed on myeloid cells, transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-related protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein Protein-coupled receptor G2 (ADGRG2), myomesin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), myosin-binding protein C, slow-twitch type (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), coiled-coil-helix-coiled-helix domain-containing protein 10, mitochondria (CHCHD10), myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cell receptor 2 (HAVCR2), lamin-B2 (LMNB2),Trefoil factor 1 (TFF1), tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocanthor protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b-binding protein beta chain (C4BPB), protein disulfide isomerase CRELD1 (CRELD1), chitinase-3-like protein 1 (CHI3L1), protein kinase C-binding protein NELL2 (NELL2), contactin-1 (CNTN1), branched-chain amino acid aminotransferase -ase, cytoplasm (BCAT1), transcription coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), innate cytotoxic trigger receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor-binding protein 1 (IGFB P1), secretin (SCT), collectin-12 (COLEC12), prolargin (PRELP), alpha-actinin-2 (ACTN2), occludin (OCLN), galectin-3 (LGALS3), cathepsin L1 (CTSL), dipeptidylaminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyroid-stimulating hormone subunit beta (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contactin-2 (CNTN2) ), percefin (PSPN), arginase-1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor-binding protein 2 (IGFBP2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neuronal adhesion molecule (NRCAM), sucoid domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), protein turtle homolog A (IGSF9),Tenacin (TNC), pyruvate kinase PKLR (PKLR), thiamine pyrophosphate kinase 1 (TPK1), UL16-binding protein 2 (ULBP2), hypoxia-inducible protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), ecto-ADP-ribosyltransferase 3 (ART3), protein kinase C-binding protein NELL1 (NELL1), macrophage scavenger receptor type I and type II (MSR1), tumor necrosis factor Sub-receptor superfamily member 10A (TNFRSF10A), hepatitis A virus cell receptor 1 (HAVCR1), peroxiredoxin-2 (PRDX2), chondroitin sulfate proteoglycan 4 (CSPG4), growth / differentiation factor 15 (GDF15), leucine-rich repeat neuron protein 1 (LRRN1), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), cadherin-related family member 2 (CDHR2), calcineurin subunit type B 1 (PPP3R Family member 9 (TNFRSF9), Brevican core protein (BCAN), Celeberin-4 (CBLN4), Creatine kinase type B (CKB), Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), Nectin-2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), Protein of unknown function C9orf40 (C9orf40), Protein DDI1 homolog 2 (DDI2), Stromélysin-1 (MMP3), Adiponectin (ADIPOQ), CMP-N-acetylneuraminate-B α-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1), layn, porphobilinogen deaminase (HMBS), tumor necrosis factor receptor superfamily member 3 (LTBR), lysosomal Pro-X carboxypeptidase (PRCP), centromere protein F (CENPF), chymotrypsin-like elastase family member 3A (CELA3A), carbonic anhydrase 12 (CA12), SLIT and NTRK-like protein 1 (SLITRK1), myomesin-2 (MYOM2),Receptor tyrosine protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin-4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor response protein 2 (RARRES2), CC motif chemokine 7 (CCL7) ), staniocalcin-1 (STC1), osteocalcin (BGLAP), interleukin-15 (IL15), protein-glutamine-gamma-glutamyltransferase 2 (TGM2), latent transformation growth factor beta-binding protein 2 (LTBP2), gamma-interferon-inducible lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin receptor B 4 (E PHB4), dystroblevin beta (DTNB), neutrophil cytoplasmic factor 2 (NCF2), mimecan (OGN), alpha-hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enablated homolog (ENAH), galectin-1 (LGALS1), hydroxyacyl glutathione hydrolase, mitochondria A (HAGH), fetuin-B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), type C lectin domain family member A (CLEC5A), disintegrin and metalloproteinase 13 with thrombospondin motif (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family molecular chaperone regulator 3 (BAG3), sclerostin (SOST),Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain protein 80 (CCDC80), odontogenic ameloblast-related protein (ODAM), cystatin-B (CSTB), seizure-like protein 6 (SEZ6L), staniocalcin-2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-related protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transport protein (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), C-type natriuretic peptide (N This includes PPC), cystatin-D (CST5), pro-low-density lipoprotein receptor-associated protein 1 (LRP1), CC-motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1 glycoprotein 1 (PSG1), gastrotropin (FABP6), ephrin-A1 (EFNA1), thrombomodulin (THBD), DNAJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholinecholine phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof, including at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 proteins. In some embodiments, one or more proteins associated with OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RFBOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, and / or BRK1, or any combination thereof.

[0037] The expression or circulation level of any one or more of these proteins can be determined by any method used to determine the expression or circulation level of a protein. In some embodiments, the expression or circulation level of a protein is determined by a proximity extension assay using oligo-conjugate antibody pairs measured by sequencing (see Sun et al., 2022). Other methods include high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC / MS), enzyme-linked immunosorbent assay (ELISA), protein immunoprecipitation, immunoelectrophoresis, Western blotting, and protein immunostaining. High-throughput proteomics includes protein pathway arrays, next-generation tissue microarrays, single-cell proteomics, single-molecule proteomics, suspension bead array technology (Luminex), multiplexed bead assays (Simoa), nanoparticles (Seer), proximity extension assays (Olink) proteomics, and aptamer-based multiplexed proteomics (Somalogic) (see, e.g., Cui et al., Lab. Invest., 2022, 102, 1170-1181, and Suhre et al., Nat. Rev. Genet., 2021, 22, 19-37).

[0038] In some embodiments, the osteoarthritis proteomics risk score is calculated using the formula: (0.76 × COL9A1 protein level) + (0.67 × CRTAC1 protein level) + (-0.26 × CNTN1 protein level) + (0.08 × GAST protein level) + (-0.45 × CYTL1 protein level) + (0.13 × KLK4 protein level) + (-0.19 × DLK1 protein level) + (0.15 × CDCP1 protein level) + (-0.19 × DPP10 protein level) + (-0.19 × CELA2A protein level) It is determined by (L) + (0.22 × RFBOX3 protein level) + (0.18 × CRELD1 protein level) + (-0.23 × NELL2 protein level) + (0.10 × PGA4 protein level) + (-0.10 × ARG1 protein level) + (-0.25 × ART3 protein level) + (0.14 × TIMD4 protein level) + (0.15 × FGFBP2 protein level) + (-0.06 × BPIFA2 protein level) + (-0.08 × PTH protein level) + (0.12 × BRK1 protein level).

[0039] In some embodiments, the osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.76 × COL9A1 protein level) + (approximately 0.67 × CRTAC1 protein level) + (approximately -0.26 × CNTN1 protein level) + (approximately 0.08 × GAST protein level) + (approximately -0.45 × CYTL1 protein level) + (approximately 0.13 × KLK4 protein level) + (approximately -0.19 × DLK1 protein level) + (approximately 0.15 × CDCP1 protein level) + (approximately -0.19 × DPP10 protein level) + (approximately -0.19 × CELA2A protein level) It is determined by (L) + (approximately 0.22 × RFBOX3 protein level) + (approximately 0.18 × CRELD1 protein level) + (approximately -0.23 × NELL2 protein level) + (approximately 0.10 × PGA4 protein level) + (approximately -0.10 × ARG1 protein level) + (approximately -0.25 × ART3 protein level) + (approximately 0.14 × TIMD4 protein level) + (approximately 0.15 × FGFBP2 protein level) + (approximately -0.06 × BPIFA2 protein level) + (approximately -0.08 × PTH protein level) + (approximately 0.12 × BRK1 protein level).

[0040] In some embodiments, the osteoarthritis proteomics risk score is expressed as follows: (approximately 0.8 × COL9A1 protein level) + (approximately 0.7 × CRTAC1 protein level) + (approximately -0.3 × CNTN1 protein level) + (approximately 0.1 × GAST protein level) + (approximately -0.4 × CYTL1 protein level) + (approximately 0.1 × KLK4 protein level) + (approximately -0.2 × DLK1 protein level) + (approximately 0.1 × CDCP1 protein level) + (approximately -0.2 × DPP10 protein level) + (approximately -0.2 × CELA2A protein level) It is determined by (L) + (approximately 0.2 × RFBOX3 protein level) + (approximately 0.2 × CRELD1 protein level) + (approximately -0.2 × NELL2 protein level) + (approximately 0.1 × PGA4 protein level) + (approximately -0.1 × ARG1 protein level) + (approximately -0.2 × ART3 protein level) + (approximately 0.1 × TIMD4 protein level) + (approximately 0.2 × FGFBP2 protein level) + (approximately -0.1 × BPIFA2 protein level) + (approximately -0.1 × PTH protein level) + (approximately 0.1 × BRK1 protein level).

[0041] The osteoarthritis proteomics risk score is determined from a biological sample obtained from a subject. In some embodiments, the methods described herein further include an initial step of obtaining a biological sample from a subject. The biological sample may contain whole cells, living cells, and / or cell debris. The biological sample may contain (or be derived from) body fluids. This disclosure includes embodiments in which the body fluid is selected from amniotic fluid, aqueous humor, vitreous fluid, bile, blood, serum, plasma, breast milk, cerebrospinal fluid, cerumen (earwax), chyle, erosion, endolymph, perilymph, exudate, feces, vaginal fluid, gastric acid, gastric juice, lymph, mucus (including rhinorrhea and sputum), pericardial fluid, peritoneal fluid, pleural fluid, pus, catarrhal secretions, saliva, sebum (skin oil), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vomit, and one or more mixtures thereof. Biological samples include cell cultures, body fluids, and cell cultures derived from body fluids. Body fluids may be obtained from mammals, for example, by venipuncture or other collection or sampling procedures. In some embodiments, biological samples include blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, swab from the cheek, or cells.

[0042] In some embodiments, the threshold osteoarthritis proteomics risk score is generated from a reference population, where members of the reference population have OA. In some embodiments, the reference population includes at least about 100 subjects. In some embodiments, the reference population includes at least about 200 subjects. In some embodiments, the reference population includes at least about 500 subjects. In some embodiments, the reference population includes at least about 1,000 subjects. In some embodiments, the reference population includes at least about 3,000 subjects. In some embodiments, the reference population includes at least about 5,000 subjects. In some embodiments, the reference population includes at least about 7,500 subjects. In some embodiments, the reference population includes at least about 10,000 subjects. In some embodiments, the reference population includes at least about 12,000 subjects. In some embodiments, the reference population includes at least about 15,000 subjects. In some embodiments, the reference population includes at least about 20,000 subjects. In some embodiments, the reference population includes at least about 30,000 subjects. In some embodiments, the reference population includes at least about 50,000 subjects. In some embodiments, the reference population includes at least about 70,000 subjects. In some embodiments, the reference population includes at least about 100,000 subjects.

[0043] The threshold proteoarthritis risk score can be determined by hierarchy. In some embodiments, the hierarchy can be represented by percentiles. In a non-limiting example, the proteoarthritis risk score can be divided into quintiles, for example, upper quintile, upper meridian quintile, meridian quintile, lower meridian quintile, and lower quintile, with the upper quintile of the proteoarthritis risk score corresponding to the highest risk group and the lower quintile of the proteoarthritis risk score corresponding to the lowest risk group.

[0044] In some embodiments, the threshold proteoarthritis risk score includes the highest weighted proteoarthritis risk score, which includes, but is not limited to, the top 50%, 55%, 60%, 70%, 80%, 90%, or 95% of the proteoarthritis risk scores from the target population. In some embodiments, the threshold proteoarthritis risk score is a value within the top 50%, 55%, 60%, 70%, 80%, 90%, or 95% percentile. In some embodiments, the threshold proteoarthritis risk score is a value within the top 50% percentile. In some embodiments, the threshold proteoarthritis risk score is a value within the top 55% percentile. In some embodiments, the threshold proteoarthritis risk score is a value within the top 60% percentile. In some embodiments, the threshold proteoarthritis risk score is within the top 65th percentile. In some embodiments, the threshold proteoarthritis risk score is within the top 70th percentile. In some embodiments, the threshold proteoarthritis risk score is within the top 75th percentile. In some embodiments, the threshold proteoarthritis risk score is within the top 80th percentile. In some embodiments, the threshold proteoarthritis risk score is within the top 85th percentile. In some embodiments, the threshold proteoarthritis risk score is within the top 90th percentile. In some embodiments, the threshold PRS is within the top 95th percentile. In some embodiments, the threshold proteoarthritis risk score is in the top 75% of the reference population. In some embodiments, the threshold proteoarthritis risk score is in the top quintile of the reference population.

[0045] Any of the methods described herein may further include administering an NGF antagonist and / or a therapeutic agent treating OA to a target patient when the target osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score. In some embodiments, the NGF antagonist includes an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

[0046] Anti-NGF antibodies can bind to NGF and inhibit NGF biological activity and / or downstream pathways mediated by NGF signaling. Numerous anti-NGF antibodies are described, for example, in PCT Publications WO00 / 073344, WO02 / 096458, WO01 / 78698, and WO01 / 64247; U.S. Patent Publications US2011 / 0206682, U.S. Patents 5,844,092, 5,877,016, and 6,153,189; Hongo et al., Hybridoma, 2000, 19, 215-227; Cell.Molec.Biol., 1993, 13, 559-568; and GenBank accession numbers U39608, U39609, L17078, and L17077. In some embodiments, the antibody is ABT-110, facinumab, tanezumab, MEDI7352, or fluranumab. In some embodiments, the antibody is facinumab. In some embodiments, the antibody is tanezumab. In some embodiments, the antibody is fluranumab. In some embodiments, the antibody is ABT-110.

[0047] Antibodies are intended to refer to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains, and two light (L) chains, interconnected by disulfide bonds, as well as their polymers (e.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region contains three domains CH1, CH2, and CH3. Each light chain contains a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region contains one domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FRs of the antibody (or its antigen-binding fragment) may be identical to those of the human germline sequence, or they may be naturally or artificially modified. The amino acid consensus sequence may be defined based on a comparative analysis of two or more CDRs.

[0048] Antibodies include an antigen-binding fragment of a complete antibody molecule. The antigen-binding portion of an antibody, or the antigen-binding fragment of an antibody, includes a naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to the antigen to form a complex. The antigen-binding fragment of an antibody may be derived from a complete antibody molecule using any appropriate standard technique, such as protein digestion or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding the variable domain and, optionally, the constant domain of the antibody. Such DNA may be available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or synthesized. The DNA may be sequenced and manipulated using chemical or molecular biological techniques, for example, to sequence one or more variable domains and / or constant domains into a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0049] Suitable NGF antagonist polypeptides are TrkA or P75 NTR This includes, but is not limited to, NGF-mimicking peptides that competitively bind to receptors. Numerous NGF antagonist peptides are described, for example, in LeSauteur et al., J. Biol. Chem., 1995, 270, 6564-6569, and Brahimi et al., Biochim. Biophys. Acta, 2010, 1800, 1018-1026, and Longo et al., J. Neurosci. Res., 1997, 48, 1-17, PCT Publications WO97 / 15593 and WO89 / 09225, and U.S. Patents 6,291,247 and 6,017,878. An additional NGF antagonist is MEDI7352.

[0050] Antisense inhibition involves reducing the target nucleic acid level in the presence of an oligonucleotide complementary to the target nucleic acid, compared to the target nucleic acid level in the absence of the oligonucleotide. Suitable small-molecule NGF antagonists are described, for example, in U.S. Publication No. 20010046959. Compounds that inhibit the binding of NGF to p75 are described in PCT Publication No. WO00 / 69829. Compounds that inhibit the binding of NGF to TrkA / p75 are described in PCT Publication No. WO98 / 17278. Additional examples of NGF antagonists include compounds described in PCT Publication Nos. WO02 / 17914 and WO02 / 20479, U.S. Patent Nos. 5,342,942, 6,127,401, and 6,359,130. Further exemplary NGF antagonists are compounds that are competitive inhibitors of NGF. See U.S. Patent No. 6,291,247. In some embodiments, the low molecular weight is K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750. In some embodiments, the low molecular weight is K252a. In some embodiments, the low molecular weight is ALE-0540. In some embodiments, the low molecular weight is PQC-083. In some embodiments, the low molecular weight is PD-90780. In some embodiments, the low molecular weight is LM11A-31 dihydrochloride. In some embodiments, the low molecular weight is Y1036. In some embodiments, the low molecular weight is GZ389988A. In some embodiments, the low molecular weight is Ro 08-2750.

[0051] Any method described herein may further include administering an NSAID and / or therapeutic agent for treating OA to a patient whose osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score. Exemplary NSAIDs include, but are not limited to, ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, or sulindac, or any combination thereof.

[0052] Any method described herein may further include administering an opioid and / or therapeutic agent for treating OA to a patient whose osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score. Exemplary opioids include, but are not limited to, codeine, hydrocodone, oxycodone, or tramadol, or any combination thereof.

[0053] Any of the methods described herein may further include administering a NaV1.8, NaV1.7 inhibitor, and / or therapeutic agent for treating OA to a target patient whose osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score. Exemplary NaV1.8 and / or NaV1.7 inhibitors include, but are not limited to, VX-548.

[0054] In some embodiments, therapeutic agents for treating OA may include analgesics, steroid injections, therapeutic injections, antidepressants, physiotherapy, strengthening exercises, radiofrequency nerve ablation, or surgery, or any combination thereof.

[0055] Examples of analgesics useful for treating osteoarthritis include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, and sulindac), acetaminophen, glucosamine, chondroitin, and opioids (such as codeine, hydrocodone, oxycodone, or tramadol), or any combination thereof.

[0056] Examples of steroid injections useful for treating OA include, but are not limited to, corticosteroids (such as triamcinolone, cortisone, prednisone, and methylprednisolone, or any combination thereof).

[0057] Examples of therapeutic injections useful for treating OA include, but are not limited to, hyaluronic acid injections. Examples of antidepressants useful for treating OA include, but are not limited to, duloxetine, amitriptyline, desipramine, and nortriptyline, or any combination thereof.

[0058] In some embodiments, treatment for OA may include physical therapy, cognitive behavioral therapy, and / or weight loss. An effective dose is an amount sufficient to produce a beneficial or desired clinical outcome, including the alleviation or reduction of pain sensation. For the purposes of this disclosure, an effective dose of an NGF antagonist (such as an anti-NGF antibody) is an amount sufficient to treat, improve, reduce the intensity of, or prevent any type of pain (including nociception and pain sensation), including acute, chronic, inflammatory, neuropathic, or postoperative pain. In some embodiments, an effective dose of an NGF antagonist is an amount of NGF antagonist that can adjust the sensitivity threshold to external stimuli to a level comparable to that observed in healthy subjects. In some embodiments, this level does not have to be comparable to that observed in healthy subjects, but is reduced compared to no combination therapy. As is understood in the art, an effective dose of an NGF antagonist may vary depending, among other factors, such as the type of pain (and patient history, as well as the type (and / or dose) of NGF antagonist used).

[0059] In the context of the methods disclosed herein, additional therapeutic agents, such as any of the agents listed above or their derivatives, may be administered immediately before, concurrently with, or immediately after the administration of the NGF antagonist (for the purposes of this disclosure, such a dosing regimen is considered to be the administration of the NGF antagonist "in combination with" the additional therapeutic agent). In some embodiments, despite the fact that the additional therapeutic agent and the NGF antagonist are administered via different routes, the additional therapeutic agent is considered to be administered "in combination with" the NGF antagonist. The methods include pharmaceutical compositions in which the NGF antagonist is co-formulated with one or more of the additional therapeutic agents described herein, and methods of use thereof.

[0060] Any of the methods described herein can be used to select subjects or candidates for a clinical trial having a patient population suitable for treatment with an NGF antagonist or other treatment regimen for OA or pain (such as chronic pain). In some embodiments, the selected candidates or subjects are divided into subgroups based on their OA proteomics risk scores for each subject or candidate, and the method is used to determine whether the subjects have an increased risk of developing OA, progression to TJR, or a different pain response. In some embodiments, subjects are selected based solely on their OA proteomics risk score. For example, if a subject or candidate has an OA proteomics risk score above a threshold, the subject is selected to initiate treatment, or the candidate is included in the clinical trial.

[0061] Furthermore, in addition to stepwise variable selection, other statistical learning or machine learning algorithms, including LASSO, Elastic Net, neural networks, and decision tree-based models such as Random Forest and XGBoost, can also be applied to construct proteomics risk scores (see Tibshirani, J. Royal Statistical Society, Series B (Methodological), 1996, 58, 267-88; Zou et al., J. Royal Statistical Society, Series B (Statistical Methodology), 2005, 67, 301-320; Castellano et al., Neurocomputing, 2000, 31, 1-13; Ooka et al., BMJ Nutrition, Prevention & Health, 2021, 4, 140-148; and Yan et al., Ann. Transl. Med., 2022, 10, 860).

[0062] All patent documents, websites, other publications, accession numbers, etc., cited above or below are referred to by reference in their entirety to the same degree as if each individual item were specifically and individually indicated to be referred to in that manner. If there are different versions of an array associated with a particular accession number over time, it means the version associated with that accession number on the effective filing date of this application. The effective filing date means the earlier of the actual filing date to which the accession number is indicated, or the filing date of the priority application, where applicable. Similarly, if different versions of a publication, website, etc., are published over time, it means the most recently published version on the effective filing date of this application, unless otherwise indicated. Any feature, process, element, embodiment, or aspect of this disclosure may be used in combination with any other feature, process, element, embodiment, or aspect unless otherwise indicated. While this disclosure has been described and illustrated in some detail for clarity and understanding, it will be apparent that certain changes and modifications may be made within the scope of the attached claims.

[0063] The following examples are provided to describe the embodiments in more detail. They are intended to illustrate, and not to limit, the claimed embodiments. The following examples provide to those skilled in the art a disclosure and explanation of how the compounds, compositions, articles, apparatus and / or methods described herein are prepared and evaluated, and are intended to be merely illustrative and not to limit any of the claims. While efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., quantity, temperature, etc.), some degree of error and variation may be expected. Unless otherwise indicated, parts are parts by weight, temperatures are °C or ambient temperature, and pressures are atmospheric pressure or near atmospheric pressure. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting any of the claimed subject matter. [Examples]

[0064] Example 1: Proteomics Risk Score Analysis Proteomics risk score analysis was performed using serum proteomics data from the UK Biobank (UKB) Pharma Proteomics Project (PPP), also known as UKB PPP (Sun et al., bioRxiv, 2022.06.17.496443). A total of 46,431 individuals and 2,939 proteins from the UKB PPP dataset passed quality control and were available for analysis.

[0065] During the initial run of model building on the training data, OA status was used as the response variable, and proteomics data for each protein were used as predictors, along with age, age squared (AgeSq), sex, body mass index (BMI), osteoarthritis polygenic risk score (OA-PRS), and the presence of principal components of the genetic data. To account for multiple testing, Bonferroni correction was used to define a statistical significance cutoff p=1.7e-5 (0.05 / 2939). After the initial run of screening, only proteins with a strong association with OA (p-value < 1.7e-5) were included as updated protein candidates. Subsequently, the following two steps were repeated until no proteins remained in the protein candidate pool to generate the final selected protein.

[0066] Step 1: From the updated protein candidates, the protein with the strongest association with OA (lowest p-value) was selected. Then, the correlation between the selected protein and the remaining updated protein candidates was determined. If there were proteins with a high correlation (>0.8) with the selected protein, these proteins were excluded from the updated protein candidates. Step 2: The selected proteins were added as covariates and excluded from the protein candidates. Steps 1 and 2 were repeated until no proteins satisfying the minimum statistical threshold remained. Based on the updated protein and covariate lists, the association between the proteins remaining in the candidate pool and the OA status can be continuously tested.

[0067] [Table 2-1]

[0068] [Table 2-2]

[0069] After all proteins were selected, the predictive model was refitted to the discovery dataset as shown in Table 2. The final OA proteomics score was calculated as follows: (0.760153 × COL9A1 protein level) + (0.674236 × CRTAC1 protein level) + (-0.259976 × CNTN1 protein level) + (0.075227 × GAST protein level) + (-0.445153 × CYTL1 protein level) + (0.134803 × KLK4 protein level) + (-0.190231 × DLK1 protein level) + (0.147944 × CDCP1 protein level) + (-0.193854 × DPP10 protein level) + (-0.189556 × CELA2A protein level) + (0.222883 × The protein level can be calculated as follows: (RBFOX3 protein level) + (0.182450 × CRELD1 protein level) + (-0.227005 × NELL2 protein level) + (0.099224 × PGA4 protein level) + (-0.099882 × ARG1 protein level) + (-0.247908 × ART3 protein level) + (0.141539 × TIMD4 protein level) + (0.151137 × FGFBP2 protein level) + (-0.063709 × BPIFA2 protein level) + (-0.081213 × PTH protein level) + (0.119394 × BRK1 protein level). Next, as shown in Figures 1 and 2, total arthroplasty was used as the endpoint to evaluate patient stratification strategies in UKB PPP OA patients.

[0070] Finally, as shown in Figures 3–8, total arthroplasty was used as an endpoint to evaluate OA proteomics score-based patient stratification in the R475-OA-1688 clinical trial. Patients in the first to third OA proteomics score quartiles treated with facinumab 1q4w showed a similar (or lower) proportion of total arthroplasty compared to patients in the first to third OA proteomics score quartiles treated with NSAIDs or placebo.

[0071] [Table 3]

[0072] In addition to identifying OA patients with a better, lower rate of joint replacement progression, patients in the first to third OA proteomics score quartiles treated with facinumab 1q4w and NSAIDs also showed a better efficacy profile (both WOMAC pain and WOMAC function scores), as shown in Figures 9 and 10. Furthermore, as shown in Figures 9 and 10, NSAID-treated patients in the highest risk quartile (fourth quartile) showed a decrease in treatment response over time, with NSAID-high risk patients (fourth quartile) showing a response rate similar to that of placebo-treated patients by week 24. Moreover, Table 4 shows that facinumab 1q4w maintains superior efficacy compared to either NSAIDs or placebo in patients in the first to third OA proteomics score quartiles.

[0073] [Table 4]

[0074] Table 5 shows that facinumab 1q4w provides an efficacy benefit compared to both NSAID-treated and placebo-treated patients, even in the high-risk group for OA proteomics scores. NSAID-treated patients in the high-risk group for OA proteomics scores do not show an improved treatment response compared to placebo-treated patients.

[0075] [Table 5]

[0076] In addition to those described herein, various modifications of the subject matter described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also included in the appended claims. Each reference cited herein (including, but not limited to, journal articles, U.S. and non-U.S. patents, published patent applications, published international patent applications, GeneBank accession numbers, and similar) is incorporated herein by reference in whole.

Claims

1. A method for determining the risk of a subject developing osteoarthritis (OA), wherein the method is: Determining or having determined the osteoarthritis proteomics risk score for the subject, wherein the osteoarthritis proteomics risk score includes a weighted aggregate value of the expression or circulating levels of one or more proteins related to OA, If the subject's osteoarthritis proteomics risk score is equal to or greater than the threshold osteoarthritis proteomics risk score, the subject's risk of developing osteoarthritis increases. The method wherein, if the subject's osteoarthritis proteomics risk score is less than the threshold osteoarthritis proteomics risk score, the subject's risk of developing osteoarthritis is reduced.

2. The one or more proteins related to OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acid protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrine-3 (MATN3), cartilage oligomeric substrate protein (COMP), and CUB domain-containing protein. Protein 1 (CDCP1), Protein BRICK1 (BRK1), Gastrin (GAST), Collagen alpha-3 (VI) chain (COL6A3), Protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), Fibroblast growth factor-binding protein 2 (FGFBP2), Annexin A10 (ANXA10), Chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), Osteopontin (SPP1), Protein Deltaho Molog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor-binding protein 4 (IGFB4), fatty acid-binding protein, heart (FABP3), trigger receptor 2 (TREM2) expressed on myeloid cells, transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-related protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGR) G2), myomesin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), myosin-binding protein C, slow-twitch type (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), coiled-coil-helix-coiled-helix domain-containing protein 10, mitochondria (CHCHD10), myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cell receptor 2 (HAVCR2), lamin-B2 (LMNB2), trefoil factor 1 (TFF1),Tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocantholone protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b-binding protein beta chain (C4BPB), protein disulfide isomerase CRED1 (CRED1), chitinase-3-like protein 1 (CHI3L1), protein kinase C-binding protein NELL2 (NELL2), contactin-1 (CNTN1), branched-chain amino acid aminotransferase, cytoplasm (BCAT1), Transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), native cytotoxic trigger receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor-binding protein 1 (IGFB1), secretin (SCT ), collectin-12 (COLEC12), prolargin (PRELP), alpha-actinin-2 (ACTN2), occludin (OCLN), galectin-3 (LGALS3), cathepsin L1 (CTSL), dipeptidylaminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyroid-stimulating hormone subunit beta (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contactin-2 (CNTN2), percefin (PS PN), arginase-1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor-binding protein 2 (IGFB2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neuronal cell adhesion molecule (NRCAM), sucoid domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), protein turtle homolog A (IGSF9), tenacin (TNC),Pyruvate kinase PKLR (PKLR), thiamine pyrophosphate kinase 1 (TPK1), UL16-binding protein 2 (ULBP2), hypoxia-inducible protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), ecto-ADP-ribosyltransferase 3 (ART3), protein kinase C-binding protein NELL1 (NELL1), macrophage scavenger receptor type I and type II (MSR1), tumor necrosis factor receptor super - Family member 10A (TNFRSF10A), Hepatitis A virus cell receptor 1 (HAVCR1), Peroxiredoxin-2 (PRDX2), Chondroitin sulfate proteoglycan 4 (CSPG4), Growth / differentiation factor 15 (GDF15), Leucine-rich repeat neuron protein 1 (LRRN1), Tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), Cadherin-related family member 2 (CDHR2), Calcineurin subunit type B 1 (PPP3R1), Tumor necrosis factor receptor superfamily Member 9 (TNFRSF9), Brevican core protein (BCAN), Seleveline-4 (CBLN4), Creatine kinase type B (CKB), Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), Nectin-2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), Protein of unknown function C9orf40 (C9orf40), Protein DDI1 homolog 2 (DDI2), Stromélysin-1 (MMP3), Adiponectin (ADIPOQ), CMP-N-acetylneuraminate-beta Galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1), Rayn, Polphobilinogen deaminase (HMBS), Tumor Necrosis Factor Receptor Superfamily Member 3 (LTBR), Lysosomal Pro-X Carboxypeptidase (PRCP), Centromere Protein F (CENPF), Chymotrypsin-like Elastase Family Member 3A (CELA3A), Carbonic Anhydrase 12 (CA12), SLIT and NTRK-like Protein 1 (SLITRK1), Myomesin-2 (MYOM2),Receptor tyrosine protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin-4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor response protein 2 (RARRES2), C-C motif chemokine 7 (CCL 7) Staniocalcin-1 (STC1), osteocalcin (BGLAP), interleukin-15 (IL15), protein-gamma-glutamyltransferase 2 (TGM2), latent transformation growth factor beta-binding protein 2 (LTBP2), gamma-interferon-inducible lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin type B receptor 4 ( EPHB4), dystroblevin beta (DTNB), neutrophil cytoplasmic factor 2 (NCF2), mimecan (OGN), alpha-hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enablated homolog (ENAH), galectin-1 (LGALS1), hydroxyacyl glutathione hydrolase, mitochondria A (HAGH), fetuin-B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), type C lectin domain family member 5 A (CLEC5A), disintegrin and metalloproteinase 13 with thrombospondin motif (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family molecular chaperone regulator 3 (BAG3), sclerostin (SOST),Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain protein 80 (CCDC80), odontogenic ameloblast-related protein (ODAM), cystatin-B (CSTB), seizure-like protein 6 (SEZ6L), staniocalcin-2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-related protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transport protein (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), type C The method according to claim 1, comprising thorium diuretic peptide (NPPC), cystatin-D (CST5), pro low-density lipoprotein receptor-related protein 1 (LRP1), C-C motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1 glycoprotein 1 (PSG1), gastrotropin (FABP6), ephrin-A1 (EFNA1), thrombomodulin (THBD), DNAJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholinecholine phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

3. The method according to claim 1, wherein the one or more proteins related to OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

4. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.760153 × COL9A1 protein level) + (approximately 0.674236 × CRTAC1 protein level) + (approximately -0.259976 × CNTN1 protein level) + (approximately 0.075227 × GAST protein level) + (approximately -0.445153 × CYTL1 protein level) + (approximately 0.134803 × KLK4 protein level) + (approximately -0.190231 × DLK1 protein level) + (approximately 0.147944 × CDCP1 protein level) + (approximately -0.193854 × DPP10 protein level) + (approximately -0.189556 × CELA2A protein level) + (approximately 0.222883 × RBF The method according to any one of claims 1 to 3, determined by (OX3 protein level) + (approximately 0.182450 × CRELD1 protein level) + (approximately -0.227005 × NELL2 protein level) + (approximately 0.099224 × PGA4 protein level) + (approximately -0.099882 × ARG1 protein level) + (approximately -0.247908 × ART3 protein level) + (approximately 0.141539 × TIMD4 protein level) + (approximately 0.151137 × FGFBP2 protein level) + (approximately -0.063709 × BPIFA2 protein level) + (approximately -0.081213 × PTH protein level) + (approximately 0.119394 × BRK1 protein level).

5. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.7602 × COL9A1 protein level) + (approximately 0.6742 × CRTAC1 protein level) + (approximately -0.2600 × CNTN1 protein level) + (approximately 0.0752 × GAST protein level) + (approximately -0.4452 × CYTL1 protein level) + (approximately 0.1348 × KLK4 protein level) + (approximately -0.1902 × DLK1 protein level) + (approximately 0.1479 × CDCP1 protein level) + (approximately -0.1939 × DPP10 protein level) + (approximately -0.1896 × CELA2A protein level) + (approximately 0.2229 × RBFO The method according to any one of claims 1 to 3, determined by (X3 protein level) + (approximately 0.1824 × CRELD1 protein level) + (approximately -0.2270 × NELL2 protein level) + (approximately 0.0992 × PGA4 protein level) + (approximately -0.0999 × ARG1 protein level) + (approximately -0.2479 × ART3 protein level) + (approximately 0.1415 × TIMD4 protein level) + (approximately 0.1511 × FGFBP2 protein level) + (approximately -0.0637 × BPIFA2 protein level) + (approximately -0.0812 × PTH protein level) + (approximately 0.1194 × BRK1 protein level).

6. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.76 × COL9A1 protein level) + (approximately 0.67 × CRTAC1 protein level) + (approximately -0.26 × CNTN1 protein level) + (approximately 0.08 × GAST protein level) + (approximately -0.45 × CYTL1 protein level) + (approximately 0.13 × KLK4 protein level) + (approximately -0.19 × DLK1 protein level) + (approximately 0.15 × CDCP1 protein level) + (approximately -0.19 × DPP10 protein level) + (approximately -0.19 × CELA2A protein level) + (approximately 0.22 × RBFOX) The method according to any one of claims 1 to 3, determined by (3 protein levels) + (approximately 0.18 × CRELD1 protein level) + (approximately -0.23 × NELL2 protein level) + (approximately 0.10 × PGA4 protein level) + (approximately -0.10 × ARG1 protein level) + (approximately -0.25 × ART3 protein level) + (approximately 0.14 × TIMD4 protein level) + (approximately 0.15 × FGFBP2 protein level) + (approximately -0.06 × BPIFA2 protein level) + (approximately -0.08 × PTH protein level) + (approximately 0.12 × BRK1 protein level).

7. The method according to any one of claims 1 to 6, wherein the osteoarthritis proteomics risk score is determined from a biological sample obtained from the subject, and the biological sample includes blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, swab from the cheek, or cells.

8. The method according to any one of claims 1 to 7, further comprising administering a nerve growth factor (NGF) antagonist and / or a therapeutic agent for treating OA to the subject if the subject's osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score.

9. The method according to claim 8, wherein the NGF antagonist comprises an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

10. The method according to claim 8, wherein the antibody is facinumab, tanezumab, MEDI7352, or fluranumab.

11. The method according to claim 8, wherein the antibody is facinumab.

12. The method according to claim 8, wherein the low molecular weight is K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

13. A method for determining the risk of a patient progressing to total joint replacement (TJR), wherein the method is: Determining or having determined the osteoarthritis proteomics risk score for the subject, wherein the osteoarthritis proteomics risk score includes a weighted aggregate value of the expression or circulating levels of one or more proteins related to OA, If the subject's osteoarthritis proteomics risk score is equal to or greater than the threshold osteoarthritis proteomics risk score, the subject's risk of progression to TJR increases. The method wherein, if the osteoarthritis proteomics risk score of the subject is less than the threshold osteoarthritis proteomics risk score, the risk of progression to TJR is reduced.

14. The one or more proteins related to OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acid protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrine-3 (MATN3), cartilage oligomeric substrate protein (COMP), and CUB domain-containing protein. Protein 1 (CDCP1), Protein BRICK1 (BRK1), Gastrin (GAST), Collagen alpha-3 (VI) chain (COL6A3), Protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), Fibroblast growth factor-binding protein 2 (FGFBP2), Annexin A10 (ANXA10), Chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), Osteopontin (SPP1), Protein Deltaho Molog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor-binding protein 4 (IGFB4), fatty acid-binding protein, heart (FABP3), trigger receptor 2 (TREM2) expressed on myeloid cells, transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-related protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGR) G2), myomesin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), myosin-binding protein C, slow-twitch type (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), coiled-coil-helix-coiled-helix domain-containing protein 10, mitochondria (CHCHD10), myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cell receptor 2 (HAVCR2), lamin-B2 (LMNB2), trefoil factor 1 (TFF1),Tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocantholone protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b-binding protein beta chain (C4BPB), protein disulfide isomerase CRED1 (CRED1), chitinase-3-like protein 1 (CHI3L1), protein kinase C-binding protein NELL2 (NELL2), contactin-1 (CNTN1), branched-chain amino acid aminotransferase, cytoplasm (BCAT1), Transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), native cytotoxic trigger receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor-binding protein 1 (IGFB1), secretin (SCT ), collectin-12 (COLEC12), prolargin (PRELP), alpha-actinin-2 (ACTN2), occludin (OCLN), galectin-3 (LGALS3), cathepsin L1 (CTSL), dipeptidylaminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyroid-stimulating hormone subunit beta (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contactin-2 (CNTN2), percefin (PS PN), arginase-1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor-binding protein 2 (IGFB2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neuronal cell adhesion molecule (NRCAM), sucoid domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), protein turtle homolog A (IGSF9), tenacin (TNC),Pyruvate kinase PKLR (PKLR), thiamine pyrophosphate kinase 1 (TPK1), UL16-binding protein 2 (ULBP2), hypoxia-inducible protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), ecto-ADP-ribosyltransferase 3 (ART3), protein kinase C-binding protein NELL1 (NELL1), macrophage scavenger receptor type I and type II (MSR1), tumor necrosis factor receptor super - Family member 10A (TNFRSF10A), Hepatitis A virus cell receptor 1 (HAVCR1), Peroxiredoxin-2 (PRDX2), Chondroitin sulfate proteoglycan 4 (CSPG4), Growth / differentiation factor 15 (GDF15), Leucine-rich repeat neuron protein 1 (LRRN1), Tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), Cadherin-related family member 2 (CDHR2), Calcineurin subunit type B 1 (PPP3R1), Tumor necrosis factor receptor superfamily Member 9 (TNFRSF9), Brevican core protein (BCAN), Seleveline-4 (CBLN4), Creatine kinase type B (CKB), Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), Nectin-2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), Protein of unknown function C9orf40 (C9orf40), Protein DDI1 homolog 2 (DDI2), Stromélysin-1 (MMP3), Adiponectin (ADIPOQ), CMP-N-acetylneuraminate-beta Galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1), Rayn, Polphobilinogen deaminase (HMBS), Tumor Necrosis Factor Receptor Superfamily Member 3 (LTBR), Lysosomal Pro-X Carboxypeptidase (PRCP), Centromere Protein F (CENPF), Chymotrypsin-like Elastase Family Member 3A (CELA3A), Carbonic Anhydrase 12 (CA12), SLIT and NTRK-like Protein 1 (SLITRK1), Myomesin-2 (MYOM2),Receptor tyrosine protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin-4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor response protein 2 (RARRES2), C-C motif chemokine 7 (CCL 7) Staniocalcin-1 (STC1), osteocalcin (BGLAP), interleukin-15 (IL15), protein-gamma-glutamyltransferase 2 (TGM2), latent transformation growth factor beta-binding protein 2 (LTBP2), gamma-interferon-inducible lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin type B receptor 4 ( EPHB4), dystroblevin beta (DTNB), neutrophil cytoplasmic factor 2 (NCF2), mimecan (OGN), alpha-hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enablated homolog (ENAH), galectin-1 (LGALS1), hydroxyacyl glutathione hydrolase, mitochondria A (HAGH), fetuin-B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), type C lectin domain family member 5 A (CLEC5A), disintegrin and metalloproteinase 13 with thrombospondin motif (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family molecular chaperone regulator 3 (BAG3), sclerostin (SOST),Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain protein 80 (CCDC80), odontogenic ameloblast-related protein (ODAM), cystatin-B (CSTB), seizure-like protein 6 (SEZ6L), staniocalcin-2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-related protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transport protein (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), type C The method according to claim 13, comprising thorium diuretic peptide (NPPC), cystatin-D (CST5), pro low-density lipoprotein receptor-related protein 1 (LRP1), C-C motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1 glycoprotein 1 (PSG1), gastrotropin (FABP6), ephrin-A1 (EFNA1), thrombomodulin (THBD), DNAJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholinecholine phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

15. The method according to claim 13, wherein the one or more proteins related to OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

16. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (0.76 × COL9A1 protein level) + (0.67 × CRTAC1 protein level) + (-0.26 × CNTN1 protein level) + (0.08 × GAST protein level) + (-0.45 × CYTL1 protein level) + (0.13 × KLK4 protein level) + (-0.19 × DLK1 protein level) + (0.15 × CDCP1 protein level) + (-0.19 × DPP10 protein level) + (-0.19 × CELA2A protein level) + (0.22 × RBFOX3 The method according to any one of claims 13 to 15, determined by (protein level) + (0.18 × CRELD1 protein level) + (-0.23 × NELL2 protein level) + (0.10 × PGA4 protein level) + (-0.10 × ARG1 protein level) + (-0.25 × ART3 protein level) + (0.14 × TIMD4 protein level) + (0.15 × FGFBP2 protein level) + (-0.06 × BPIFA2 protein level) + (-0.08 × PTH protein level) + (0.12 × BRK1 protein level).

17. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.76 × COL9A1 protein level) + (approximately 0.67 × CRTAC1 protein level) + (approximately -0.26 × CNTN1 protein level) + (approximately 0.08 × GAST protein level) + (approximately -0.45 × CYTL1 protein level) + (approximately 0.13 × KLK4 protein level) + (approximately -0.19 × DLK1 protein level) + (approximately 0.15 × CDCP1 protein level) + (approximately -0.19 × DPP10 protein level) + (approximately -0.19 × CELA2A protein level) + (approximately 0.22 × RBFOX3) The method according to any one of claims 13 to 15, determined by (protein level) + (approximately 0.18 × CRELD1 protein level) + (approximately -0.23 × NELL2 protein level) + (approximately 0.10 × PGA4 protein level) + (approximately -0.10 × ARG1 protein level) + (approximately -0.25 × ART3 protein level) + (approximately 0.14 × TIMD4 protein level) + (approximately 0.15 × FGFBP2 protein level) + (approximately -0.06 × BPIFA2 protein level) + (approximately -0.08 × PTH protein level) + (approximately 0.12 × BRK1 protein level).

18. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.8 × COL9A1 protein level) + (approximately 0.7 × CRTAC1 protein level) + (approximately -0.3 × CNTN1 protein level) + (approximately 0.1 × GAST protein level) + (approximately -0.4 × CYTL1 protein level) + (approximately 0.1 × KLK4 protein level) + (approximately -0.2 × DLK1 protein level) + (approximately 0.1 × CDCP1 protein level) + (approximately -0.2 × DPP10 protein level) + (approximately -0.2 × CELA2A protein level) + (approximately 0.2 × RBFOX3) The method according to any one of claims 13 to 15, determined by (protein level) + (approximately 0.2 × CRELD1 protein level) + (approximately -0.2 × NELL2 protein level) + (approximately 0.1 × PGA4 protein level) + (approximately -0.1 × ARG1 protein level) + (approximately -0.2 × ART3 protein level) + (approximately 0.1 × TIMD4 protein level) + (approximately 0.2 × FGFBP2 protein level) + (approximately -0.1 × BPIFA2 protein level) + (approximately -0.1 × PTH protein level) + (approximately 0.1 × BRK1 protein level).

19. The method according to any one of claims 13 to 18, wherein the osteoarthritis proteomics risk score is determined from a biological sample obtained from the subject, and the biological sample includes blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, swab from the cheek, or cells.

20. The method according to any one of claims 13 to 19, further comprising administering a nerve growth factor (NGF) antagonist and / or a therapeutic agent for treating OA to the subject if the subject's osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score.

21. The method according to claim 20, wherein the NGF antagonist is an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

22. The method according to claim 21, wherein the antibody is facinumab, tanezumab, MEDI7352, or fluranumab.

23. The method according to claim 21, wherein the antibody is facinumab.

24. The method according to claim 21, wherein the low molecular weight is K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

25. A method for determining the treatment response of a subject treated with a nerve growth factor (NGF) antagonist, wherein the method is: Determining or having determined the osteoarthritis proteomics risk score for the subject, wherein the osteoarthritis proteomics risk score includes a weighted aggregate value of the expression or circulating levels of one or more proteins related to OA, If the osteoarthritis proteomics risk score of the subject is equal to or greater than the threshold osteoarthritis proteomics risk score, the subject will have a low response to the NGF antagonist. The method wherein, if the osteoarthritis proteomics risk score of the subject is less than the threshold osteoarthritis proteomics risk score, the subject's response to the NGF antagonist increases.

26. The one or more proteins related to OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acid protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrine-3 (MATN3), cartilage oligomeric substrate protein (COMP), and CUB domain-containing protein. Protein 1 (CDCP1), Protein BRICK1 (BRK1), Gastrin (GAST), Collagen alpha-3 (VI) chain (COL6A3), Protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), Fibroblast growth factor-binding protein 2 (FGFBP2), Annexin A10 (ANXA10), Chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), Osteopontin (SPP1), Protein Deltaho Molog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor-binding protein 4 (IGFB4), fatty acid-binding protein, heart (FABP3), trigger receptor 2 (TREM2) expressed on myeloid cells, transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-related protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGR) G2), myomesin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), myosin-binding protein C, slow-twitch type (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), coiled-coil-helix-coiled-helix domain-containing protein 10, mitochondria (CHCHD10), myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cell receptor 2 (HAVCR2), lamin-B2 (LMNB2), trefoil factor 1 (TFF1),Tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocantholone protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b-binding protein beta chain (C4BPB), protein disulfide isomerase CRED1 (CRED1), chitinase-3-like protein 1 (CHI3L1), protein kinase C-binding protein NELL2 (NELL2), contactin-1 (CNTN1), branched-chain amino acid aminotransferase, cytoplasm (BCAT1), Transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), native cytotoxic trigger receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor-binding protein 1 (IGFB1), secretin (SCT ), collectin-12 (COLEC12), prolargin (PRELP), alpha-actinin-2 (ACTN2), occludin (OCLN), galectin-3 (LGALS3), cathepsin L1 (CTSL), dipeptidylaminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyroid-stimulating hormone subunit beta (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contactin-2 (CNTN2), percefin (PS PN), arginase-1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor-binding protein 2 (IGFB2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neuronal cell adhesion molecule (NRCAM), sucoid domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), protein turtle homolog A (IGSF9), tenacin (TNC),Pyruvate kinase PKLR (PKLR), thiamine pyrophosphate kinase 1 (TPK1), UL16-binding protein 2 (ULBP2), hypoxia-inducible protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), ecto-ADP-ribosyltransferase 3 (ART3), protein kinase C-binding protein NELL1 (NELL1), macrophage scavenger receptor type I and type II (MSR1), tumor necrosis factor receptor super - Family member 10A (TNFRSF10A), Hepatitis A virus cell receptor 1 (HAVCR1), Peroxiredoxin-2 (PRDX2), Chondroitin sulfate proteoglycan 4 (CSPG4), Growth / differentiation factor 15 (GDF15), Leucine-rich repeat neuron protein 1 (LRRN1), Tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), Cadherin-related family member 2 (CDHR2), Calcineurin subunit type B 1 (PPP3R1), Tumor necrosis factor receptor superfamily Member 9 (TNFRSF9), Brevican core protein (BCAN), Seleveline-4 (CBLN4), Creatine kinase type B (CKB), Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), Nectin-2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), Protein of unknown function C9orf40 (C9orf40), Protein DDI1 homolog 2 (DDI2), Stromélysin-1 (MMP3), Adiponectin (ADIPOQ), CMP-N-acetylneuraminate-beta Galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1), Rayn, Polphobilinogen deaminase (HMBS), Tumor Necrosis Factor Receptor Superfamily Member 3 (LTBR), Lysosomal Pro-X Carboxypeptidase (PRCP), Centromere Protein F (CENPF), Chymotrypsin-like Elastase Family Member 3A (CELA3A), Carbonic Anhydrase 12 (CA12), SLIT and NTRK-like Protein 1 (SLITRK1), Myomesin-2 (MYOM2),Receptor tyrosine protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin-4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor response protein 2 (RARRES2), C-C motif chemokine 7 (CCL 7) Staniocalcin-1 (STC1), osteocalcin (BGLAP), interleukin-15 (IL15), protein-gamma-glutamyltransferase 2 (TGM2), latent transformation growth factor beta-binding protein 2 (LTBP2), gamma-interferon-inducible lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin type B receptor 4 ( EPHB4), dystroblevin beta (DTNB), neutrophil cytoplasmic factor 2 (NCF2), mimecan (OGN), alpha-hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enablated homolog (ENAH), galectin-1 (LGALS1), hydroxyacyl glutathione hydrolase, mitochondria A (HAGH), fetuin-B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), type C lectin domain family member 5 A (CLEC5A), disintegrin and metalloproteinase 13 with thrombospondin motif (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family molecular chaperone regulator 3 (BAG3), sclerostin (SOST),Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain protein 80 (CCDC80), odontogenic ameloblast-related protein (ODAM), cystatin-B (CSTB), seizure-like protein 6 (SEZ6L), staniocalcin-2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-related protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transport protein (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), type C The method according to claim 25, comprising thorium diuretic peptide (NPPC), cystatin-D (CST5), pro low-density lipoprotein receptor-related protein 1 (LRP1), C-C motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1 glycoprotein 1 (PSG1), gastrotropin (FABP6), ephrin-A1 (EFNA1), thrombomodulin (THBD), DNAJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholinecholine phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

27. The method according to claim 25, wherein the one or more proteins related to OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

28. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (0.76 × COL9A1 protein level) + (0.67 × CRTAC1 protein level) + (-0.26 × CNTN1 protein level) + (0.08 × GAST protein level) + (-0.45 × CYTL1 protein level) + (0.13 × KLK4 protein level) + (-0.19 × DLK1 protein level) + (0.15 × CDCP1 protein level) + (-0.19 × DPP10 protein level) + (-0.19 × CELA2A protein level) + (0.22 × RBFOX3 The method according to any one of claims 25 to 27, determined by (protein level) + (0.18 × CRELD1 protein level) + (-0.23 × NELL2 protein level) + (0.10 × PGA4 protein level) + (-0.10 × ARG1 protein level) + (-0.25 × ART3 protein level) + (0.14 × TIMD4 protein level) + (0.15 × FGFBP2 protein level) + (-0.06 × BPIFA2 protein level) + (-0.08 × PTH protein level) + (0.12 × BRK1 protein level).

29. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.76 × COL9A1 protein level) + (approximately 0.67 × CRTAC1 protein level) + (approximately -0.26 × CNTN1 protein level) + (approximately 0.08 × GAST protein level) + (approximately -0.45 × CYTL1 protein level) + (approximately 0.13 × KLK4 protein level) + (approximately -0.19 × DLK1 protein level) + (approximately 0.15 × CDCP1 protein level) + (approximately -0.19 × DPP10 protein level) + (approximately -0.19 × CELA2A protein level) + (approximately 0.22 × RBFOX3) The method according to any one of claims 25 to 27, determined by (protein level) + (approximately 0.18 × CRELD1 protein level) + (approximately -0.23 × NELL2 protein level) + (approximately 0.10 × PGA4 protein level) + (approximately -0.10 × ARG1 protein level) + (approximately -0.25 × ART3 protein level) + (approximately 0.14 × TIMD4 protein level) + (approximately 0.15 × FGFBP2 protein level) + (approximately -0.06 × BPIFA2 protein level) + (approximately -0.08 × PTH protein level) + (approximately 0.12 × BRK1 protein level).

30. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.8 × COL9A1 protein level) + (approximately 0.7 × CRTAC1 protein level) + (approximately -0.3 × CNTN1 protein level) + (approximately 0.1 × GAST protein level) + (approximately -0.4 × CYTL1 protein level) + (approximately 0.1 × KLK4 protein level) + (approximately -0.2 × DLK1 protein level) + (approximately 0.1 × CDCP1 protein level) + (approximately -0.2 × DPP10 protein level) + (approximately -0.2 × CELA2A protein level) + (approximately 0.2 × RBFOX3) The method according to any one of claims 25 to 27, determined by (protein level) + (approximately 0.2 × CRELD1 protein level) + (approximately -0.2 × NELL2 protein level) + (approximately 0.1 × PGA4 protein level) + (approximately -0.1 × ARG1 protein level) + (approximately -0.2 × ART3 protein level) + (approximately 0.1 × TIMD4 protein level) + (approximately 0.2 × FGFBP2 protein level) + (approximately -0.1 × BPIFA2 protein level) + (approximately -0.1 × PTH protein level) + (approximately 0.1 × BRK1 protein level).

31. The method according to any one of claims 25 to 30, wherein the osteoarthritis proteomics risk score is determined from a biological sample obtained from the subject, and the biological sample includes blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, swab from the cheek, or cells.

32. The method according to any one of claims 25 to 31, wherein the NGF antagonist comprises an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, a siRNA molecule, or a small molecule.

33. The method according to claim 32, wherein the antibody comprises facinumab, tanezumab, MEDI7352, or fluranumab.

34. The method according to claim 32, wherein the antibody comprises facinumab.

35. The method according to claim 32, wherein the low molecular weight includes K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

36. A method for determining the treatment response of a subject treated with a nonsteroidal anti-inflammatory drug (NSAID), wherein the method is: Determining or having determined the osteoarthritis proteomics risk score for the subject, wherein the osteoarthritis proteomics risk score includes a weighted aggregate value of the expression or circulating levels of one or more proteins related to OA, If the subject's osteoarthritis proteomics risk score is equal to or greater than the threshold osteoarthritis proteomics risk score, the subject's response to NSAIDs decreases. The method wherein, if the subject's osteoarthritis proteomics risk score is less than the threshold osteoarthritis proteomics risk score, the subject's response to an NSAID increases.

37. The one or more proteins related to OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acid protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrine-3 (MATN3), cartilage oligomeric substrate protein (COMP), and CUB domain-containing protein. Protein 1 (CDCP1), Protein BRICK1 (BRK1), Gastrin (GAST), Collagen alpha-3 (VI) chain (COL6A3), Protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), Fibroblast growth factor-binding protein 2 (FGFBP2), Annexin A10 (ANXA10), Chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), Osteopontin (SPP1), Protein Deltaho Molog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor-binding protein 4 (IGFB4), fatty acid-binding protein, heart (FABP3), trigger receptor 2 (TREM2) expressed on myeloid cells, transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-related protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGR) G2), myomesin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), myosin-binding protein C, slow-twitch type (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), coiled-coil-helix-coiled-helix domain-containing protein 10, mitochondria (CHCHD10), myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cell receptor 2 (HAVCR2), lamin-B2 (LMNB2), trefoil factor 1 (TFF1),Tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocantholone protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b-binding protein beta chain (C4BPB), protein disulfide isomerase CRED1 (CRED1), chitinase-3-like protein 1 (CHI3L1), protein kinase C-binding protein NELL2 (NELL2), contactin-1 (CNTN1), branched-chain amino acid aminotransferase, cytoplasm (BCAT1), Transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), native cytotoxic trigger receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor-binding protein 1 (IGFB1), secretin (SCT ), collectin-12 (COLEC12), prolargin (PRELP), alpha-actinin-2 (ACTN2), occludin (OCLN), galectin-3 (LGALS3), cathepsin L1 (CTSL), dipeptidylaminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyroid-stimulating hormone subunit beta (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contactin-2 (CNTN2), percefin (PS PN), arginase-1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor-binding protein 2 (IGFB2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neuronal cell adhesion molecule (NRCAM), sucoid domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), protein turtle homolog A (IGSF9), tenacin (TNC),Pyruvate kinase PKLR (PKLR), thiamine pyrophosphate kinase 1 (TPK1), UL16-binding protein 2 (ULBP2), hypoxia-inducible protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), ecto-ADP-ribosyltransferase 3 (ART3), protein kinase C-binding protein NELL1 (NELL1), macrophage scavenger receptor type I and type II (MSR1), tumor necrosis factor receptor super - Family member 10A (TNFRSF10A), Hepatitis A virus cell receptor 1 (HAVCR1), Peroxiredoxin-2 (PRDX2), Chondroitin sulfate proteoglycan 4 (CSPG4), Growth / differentiation factor 15 (GDF15), Leucine-rich repeat neuron protein 1 (LRRN1), Tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), Cadherin-related family member 2 (CDHR2), Calcineurin subunit type B 1 (PPP3R1), Tumor necrosis factor receptor superfamily Member 9 (TNFRSF9), Brevican core protein (BCAN), Seleveline-4 (CBLN4), Creatine kinase type B (CKB), Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), Nectin-2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), Protein of unknown function C9orf40 (C9orf40), Protein DDI1 homolog 2 (DDI2), Stromélysin-1 (MMP3), Adiponectin (ADIPOQ), CMP-N-acetylneuraminate-beta Galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1), Rayn, Polphobilinogen deaminase (HMBS), Tumor Necrosis Factor Receptor Superfamily Member 3 (LTBR), Lysosomal Pro-X Carboxypeptidase (PRCP), Centromere Protein F (CENPF), Chymotrypsin-like Elastase Family Member 3A (CELA3A), Carbonic Anhydrase 12 (CA12), SLIT and NTRK-like Protein 1 (SLITRK1), Myomesin-2 (MYOM2),Receptor tyrosine protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin-4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor response protein 2 (RARRES2), C-C motif chemokine 7 (CCL 7) Staniocalcin-1 (STC1), osteocalcin (BGLAP), interleukin-15 (IL15), protein-gamma-glutamyltransferase 2 (TGM2), latent transformation growth factor beta-binding protein 2 (LTBP2), gamma-interferon-inducible lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin type B receptor 4 ( EPHB4), dystroblevin beta (DTNB), neutrophil cytoplasmic factor 2 (NCF2), mimecan (OGN), alpha-hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enablated homolog (ENAH), galectin-1 (LGALS1), hydroxyacyl glutathione hydrolase, mitochondria A (HAGH), fetuin-B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), type C lectin domain family member 5 A (CLEC5A), disintegrin and metalloproteinase 13 with thrombospondin motif (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family molecular chaperone regulator 3 (BAG3), sclerostin (SOST),Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain protein 80 (CCDC80), odontogenic ameloblast-related protein (ODAM), cystatin-B (CSTB), seizure-like protein 6 (SEZ6L), staniocalcin-2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-related protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transport protein (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), type C The method according to claim 36, comprising thorium diuretic peptide (NPPC), cystatin-D (CST5), pro low-density lipoprotein receptor-related protein 1 (LRP1), C-C motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1 glycoprotein 1 (PSG1), gastrotropin (FABP6), ephrin-A1 (EFNA1), thrombomodulin (THBD), DNAJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholinecholine phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

38. The method according to claim 36, wherein the one or more proteins related to OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

39. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (0.76 × COL9A1 protein level) + (0.67 × CRTAC1 protein level) + (-0.26 × CNTN1 protein level) + (0.08 × GAST protein level) + (-0.45 × CYTL1 protein level) + (0.13 × KLK4 protein level) + (-0.19 × DLK1 protein level) + (0.15 × CDCP1 protein level) + (-0.19 × DPP10 protein level) + (-0.19 × CELA2A protein level) + (0.22 × RBFOX3 The method according to any one of claims 36 to 38, determined by (protein level) + (0.18 × CRELD1 protein level) + (-0.23 × NELL2 protein level) + (0.10 × PGA4 protein level) + (-0.10 × ARG1 protein level) + (-0.25 × ART3 protein level) + (0.14 × TIMD4 protein level) + (0.15 × FGFBP2 protein level) + (-0.06 × BPIFA2 protein level) + (-0.08 × PTH protein level) + (0.12 × BRK1 protein level).

40. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.76 × COL9A1 protein level) + (approximately 0.67 × CRTAC1 protein level) + (approximately -0.26 × CNTN1 protein level) + (approximately 0.08 × GAST protein level) + (approximately -0.45 × CYTL1 protein level) + (approximately 0.13 × KLK4 protein level) + (approximately -0.19 × DLK1 protein level) + (approximately 0.15 × CDCP1 protein level) + (approximately -0.19 × DPP10 protein level) + (approximately -0.19 × CELA2A protein level) + (approximately 0.22 × RBFOX3) The method according to any one of claims 36 to 38, determined by (protein level) + (approximately 0.18 × CRELD1 protein level) + (approximately -0.23 × NELL2 protein level) + (approximately 0.10 × PGA4 protein level) + (approximately -0.10 × ARG1 protein level) + (approximately -0.25 × ART3 protein level) + (approximately 0.14 × TIMD4 protein level) + (approximately 0.15 × FGFBP2 protein level) + (approximately -0.06 × BPIFA2 protein level) + (approximately -0.08 × PTH protein level) + (approximately 0.12 × BRK1 protein level).

41. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.8 × COL9A1 protein level) + (approximately 0.7 × CRTAC1 protein level) + (approximately -0.3 × CNTN1 protein level) + (approximately 0.1 × GAST protein level) + (approximately -0.4 × CYTL1 protein level) + (approximately 0.1 × KLK4 protein level) + (approximately -0.2 × DLK1 protein level) + (approximately 0.1 × CDCP1 protein level) + (approximately -0.2 × DPP10 protein level) + (approximately -0.2 × CELA2A protein level) + (approximately 0.2 × RBFOX3) The method according to any one of claims 36 to 38, determined by (protein level) + (approximately 0.2 × CRELD1 protein level) + (approximately -0.2 × NELL2 protein level) + (approximately 0.1 × PGA4 protein level) + (approximately -0.1 × ARG1 protein level) + (approximately -0.2 × ART3 protein level) + (approximately 0.1 × TIMD4 protein level) + (approximately 0.2 × FGFBP2 protein level) + (approximately -0.1 × BPIFA2 protein level) + (approximately -0.1 × PTH protein level) + (approximately 0.1 × BRK1 protein level).

42. The method according to any one of claims 36 to 41, wherein the osteoarthritis proteomics risk score is determined from a biological sample obtained from the subject, and the biological sample includes blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, swab from the cheek, or cells.

43. The method according to any one of claims 36 to 42, wherein the NSAID comprises ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, or sulindac, or any combination thereof.

44. A method for determining the treatment response (pain and functional improvement) of a subject, wherein the method is: Determining or having determined the osteoarthritis proteomics risk score for the subject, wherein the osteoarthritis proteomics risk score includes a weighted aggregate value of the expression or circulating levels of one or more proteins related to OA, If the osteoarthritis proteomics risk score of the subject is equal to or greater than the threshold osteoarthritis proteomics risk score, the subject will have a poor treatment response. The method wherein, if the osteoarthritis proteomics risk score of the subject is less than the threshold osteoarthritis proteomics risk score, the subject has an increased treatment response.

45. The one or more proteins related to OA include collagen alpha-1 (IX) chain (COL9A1), cartilage acid protein 1 (CRTAC1), scrapie-responsive protein 1 (SCRG1), aggrecan core protein (ACAN), CCN family member 3 (CCN3), chromogranin-A (CHGA), kallikrein-4 (KLK4), RNA-binding protein fox-1 homolog 3 (RBFOX3), decorin (DCN), matrine-3 (MATN3), cartilage oligomeric substrate protein (COMP), and CUB domain-containing protein. Protein 1 (CDCP1), Protein BRICK1 (BRK1), Gastrin (GAST), Collagen alpha-3 (VI) chain (COL6A3), Protein AMBP (AMBP), V-set and immunoglobulin domain-containing protein 2 (VSIG2), Fibroblast growth factor-binding protein 2 (FGFBP2), Annexin A10 (ANXA10), Chymotrypsin-like elastase family member 2A (CELA2A), T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4), Osteopontin (SPP1), Protein Deltaho Molog 1 (DLK1), pepsin A-4 (PGA4), elastin (ELN), insulin-like growth factor-binding protein 4 (IGFB4), fatty acid-binding protein, heart (FABP3), trigger receptor 2 (TREM2) expressed on myeloid cells, transmembrane glycoprotein NMB (GPNMB), cytokine-like protein 1 (CYTL1), cytoskeleton-related protein 4 (CKAP4), CD276 antigen (CD276), ephrin type A receptor 2 (EPHA2), heat shock protein beta-6 (HSPB6), adhesion G protein-coupled receptor G2 (ADGR) G2), myomesin-3 (MYOM3), leukotriene A-4 hydrolase (LTA4H), myosin-binding protein C, slow-twitch type (MYBPC1), collagenase 3 (MMP13), neuronal calcium sensor 1 (NCS1), coiled-coil-helix-coiled-helix domain-containing protein 10, mitochondria (CHCHD10), myosin light chain 3 (MYL3), macrophage metalloelastase (MMP12), hepatitis A virus cell receptor 2 (HAVCR2), lamin-B2 (LMNB2), trefoil factor 1 (TFF1),Tumor necrosis factor receptor superfamily member 27 (EDA2R), neurocantholone protein (NCAN), asialoglycoprotein receptor 1 (ASGR1), angiotensin-converting enzyme 2 (ACE2), C4b-binding protein beta chain (C4BPB), protein disulfide isomerase CRED1 (CRED1), chitinase-3-like protein 1 (CHI3L1), protein kinase C-binding protein NELL2 (NELL2), contactin-1 (CNTN1), branched-chain amino acid aminotransferase, cytoplasm (BCAT1), Transcriptional coactivator YAP1 (YAP1), CD302 antigen (CD302), lactoperoxidase (LPO), native cytotoxic trigger receptor 3 ligand 1 (NCR3LG1), MANSC domain-containing protein 4 (MANSC4), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), uromodulin (UMOD), amphiregulin (AREG), disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), insulin-like growth factor-binding protein 1 (IGFB1), secretin (SCT ), collectin-12 (COLEC12), prolargin (PRELP), alpha-actinin-2 (ACTN2), occludin (OCLN), galectin-3 (LGALS3), cathepsin L1 (CTSL), dipeptidylaminopeptidase-like protein 6 (DPP6), transthyretin (TTR), gastric triacylglycerol lipase (LIPF), thyroid-stimulating hormone subunit beta (TSHB), urokinase plasminogen activator surface receptor (PLAUR), contactin-2 (CNTN2), percefin (PS PN), arginase-1 (ARG1), uteroglobin (SCGB1A1), BPI fold-containing family A member 2 (BPIFA2), follistatin (FST), insulin-like growth factor-binding protein 2 (IGFB2), anterior gradient protein 2 homolog (AGR2), trefoil factor 2 (TFF2), neuronal cell adhesion molecule (NRCAM), sucoid domain-containing protein 5 (SUSD5), leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), protein turtle homolog A (IGSF9), tenacin (TNC),Pyruvate kinase PKLR (PKLR), thiamine pyrophosphate kinase 1 (TPK1), UL16-binding protein 2 (ULBP2), hypoxia-inducible protein 1 (HYOU1), inactive dipeptidyl peptidase 10 (DPP10), flavin reductase (NADPH) (BLVRB), carbonic anhydrase 1 (CA1), ecto-ADP-ribosyltransferase 3 (ART3), protein kinase C-binding protein NELL1 (NELL1), macrophage scavenger receptor type I and type II (MSR1), tumor necrosis factor receptor super - Family member 10A (TNFRSF10A), Hepatitis A virus cell receptor 1 (HAVCR1), Peroxiredoxin-2 (PRDX2), Chondroitin sulfate proteoglycan 4 (CSPG4), Growth / differentiation factor 15 (GDF15), Leucine-rich repeat neuron protein 1 (LRRN1), Tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), Cadherin-related family member 2 (CDHR2), Calcineurin subunit type B 1 (PPP3R1), Tumor necrosis factor receptor superfamily Member 9 (TNFRSF9), Brevican core protein (BCAN), Seleveline-4 (CBLN4), Creatine kinase type B (CKB), Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9), Nectin-2 (NECTIN2), Down syndrome cell adhesion molecule (DSCAM), Protein of unknown function C9orf40 (C9orf40), Protein DDI1 homolog 2 (DDI2), Stromélysin-1 (MMP3), Adiponectin (ADIPOQ), CMP-N-acetylneuraminate-beta Galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1), Rayn, Polphobilinogen deaminase (HMBS), Tumor Necrosis Factor Receptor Superfamily Member 3 (LTBR), Lysosomal Pro-X Carboxypeptidase (PRCP), Centromere Protein F (CENPF), Chymotrypsin-like Elastase Family Member 3A (CELA3A), Carbonic Anhydrase 12 (CA12), SLIT and NTRK-like Protein 1 (SLITRK1), Myomesin-2 (MYOM2),Receptor tyrosine protein kinase erbB-4 (ERBB4), lysosomal membrane protein 2 (SCARB2), collagen alpha-1 (XVIII) chain (COL18A1), low-density lipoprotein receptor-related protein 11 (LRP11), thrombospondin-4 (THBS4), pleiotrophin (PTN), phosphoethanolamine / phosphocholine phosphatase (PHOSPHO1), asialoglycoprotein receptor 2 (ASGR2), retinoic acid receptor response protein 2 (RARRES2), C-C motif chemokine 7 (CCL 7) Staniocalcin-1 (STC1), osteocalcin (BGLAP), interleukin-15 (IL15), protein-gamma-glutamyltransferase 2 (TGM2), latent transformation growth factor beta-binding protein 2 (LTBP2), gamma-interferon-inducible lysosomal thiol reductase (IFI30), serine protease inhibitor Kazal type 5 (SPINK5), WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1), ephrin type B receptor 4 ( EPHB4), dystroblevin beta (DTNB), neutrophil cytoplasmic factor 2 (NCF2), mimecan (OGN), alpha-hemoglobin stabilizing protein (AHSP), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), tectonic-3 (TCTN3), AMP deaminase 3 (AMPD3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), protein enablated homolog (ENAH), galectin-1 (LGALS1), hydroxyacyl glutathione hydrolase, mitochondria A (HAGH), fetuin-B (FETUB), fibronectin type III domain-containing protein 1 (FNDC1), type C lectin domain family member 5 A (CLEC5A), disintegrin and metalloproteinase 13 with thrombospondin motif (ADAMTS13), cysteine ​​and glycine-rich protein 3 (CSRP3), keratin, type I cytoskeleton 19 (KRT19), cytokine receptor-like factor 1 (CRLF1), BAG family molecular chaperone regulator 3 (BAG3), sclerostin (SOST),Fc receptor-like protein 5 (FCRL5), acetylcholinesterase (ACHE), actin, aortic smooth muscle (ACTA2), coiled-coil domain protein 80 (CCDC80), odontogenic ameloblast-related protein (ODAM), cystatin-B (CSTB), seizure-like protein 6 (SEZ6L), staniocalcin-2 (STC2), myosin light chain 4 (MYL4), retinal dehydrogenase 1 (ALDH1A1), matrix remodeling-related protein 8 (MXRA8), macrophage capping protein (CAPG), band 3 anion transport protein (SLC4A1), chymotrypsinogen B (CTRB1), trefoil factor 3 (TFF3), type C The method according to claim 44, comprising thorium diuretic peptide (NPPC), cystatin-D (CST5), pro low-density lipoprotein receptor-related protein 1 (LRP1), C-C motif chemokine 5 (CCL5), carbonic anhydrase 2 (CA2), pregnancy-specific beta-1 glycoprotein 1 (PSG1), gastrotropin (FABP6), ephrin-A1 (EFNA1), thrombomodulin (THBD), DNAJ homolog subfamily A member 4 (DNAJA4), interleukin-4 receptor subunit alpha (IL4R), glycerophosphocholinecholine phosphodiesterase ENPP6 (ENPP6), or parathyroid hormone (PTH), or any combination thereof.

46. The method according to claim 44, wherein the one or more proteins related to OA include COL9A1, CRTAC1, CNTN1, GAST, CYTL1, KLK4, DLK1, CDCP1, DPP10, CELA2A, RBFOX3, CRELD1, NELL2, PGA4, ARG1, ART3, TIMD4, FGFBP2, BPIFA2, PTH, or BRK1, or any combination thereof.

47. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (0.76 × COL9A1 protein level) + (0.67 × CRTAC1 protein level) + (-0.26 × CNTN1 protein level) + (0.08 × GAST protein level) + (-0.45 × CYTL1 protein level) + (0.13 × KLK4 protein level) + (-0.19 × DLK1 protein level) + (0.15 × CDCP1 protein level) + (-0.19 × DPP10 protein level) + (-0.19 × CELA2A protein level) + (0.22 × RBFOX3 The method according to any one of claims 44 to 46, determined by (protein level) + (0.18 × CRELD1 protein level) + (-0.23 × NELL2 protein level) + (0.10 × PGA4 protein level) + (-0.10 × ARG1 protein level) + (-0.25 × ART3 protein level) + (0.14 × TIMD4 protein level) + (0.15 × FGFBP2 protein level) + (-0.06 × BPIFA2 protein level) + (-0.08 × PTH protein level) + (0.12 × BRK1 protein level).

48. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.76 × COL9A1 protein level) + (approximately 0.67 × CRTAC1 protein level) + (approximately -0.26 × CNTN1 protein level) + (approximately 0.08 × GAST protein level) + (approximately -0.45 × CYTL1 protein level) + (approximately 0.13 × KLK4 protein level) + (approximately -0.19 × DLK1 protein level) + (approximately 0.15 × CDCP1 protein level) + (approximately -0.19 × DPP10 protein level) + (approximately -0.19 × CELA2A protein level) + (approximately 0.22 × RBFOX3) The method according to any one of claims 44 to 46, determined by (protein level) + (approximately 0.18 × CRELD1 protein level) + (approximately -0.23 × NELL2 protein level) + (approximately 0.10 × PGA4 protein level) + (approximately -0.10 × ARG1 protein level) + (approximately -0.25 × ART3 protein level) + (approximately 0.14 × TIMD4 protein level) + (approximately 0.15 × FGFBP2 protein level) + (approximately -0.06 × BPIFA2 protein level) + (approximately -0.08 × PTH protein level) + (approximately 0.12 × BRK1 protein level).

49. The aforementioned osteoarthritis proteomics risk score is calculated using the formula: (approximately 0.8 × COL9A1 protein level) + (approximately 0.7 × CRTAC1 protein level) + (approximately -0.3 × CNTN1 protein level) + (approximately 0.1 × GAST protein level) + (approximately -0.4 × CYTL1 protein level) + (approximately 0.1 × KLK4 protein level) + (approximately -0.2 × DLK1 protein level) + (approximately 0.1 × CDCP1 protein level) + (approximately -0.2 × DPP10 protein level) + (approximately -0.2 × CELA2A protein level) + (approximately 0.2 × RBFOX3) The method according to any one of claims 44 to 46, determined by (protein level) + (approximately 0.2 × CRELD1 protein level) + (approximately -0.2 × NELL2 protein level) + (approximately 0.1 × PGA4 protein level) + (approximately -0.1 × ARG1 protein level) + (approximately -0.2 × ART3 protein level) + (approximately 0.1 × TIMD4 protein level) + (approximately 0.2 × FGFBP2 protein level) + (approximately -0.1 × BPIFA2 protein level) + (approximately -0.1 × PTH protein level) + (approximately 0.1 × BRK1 protein level).

50. The method according to any one of claims 44 to 49, wherein the osteoarthritis proteomics risk score is determined from a biological sample obtained from the subject, the biological sample comprising blood, serum, plasma, semen, saliva, urine, feces, hair, teeth, bone, tissue, swab from the cheek, or cells.

51. The method according to any one of claims 44 to 50, further comprising administering a nerve growth factor (NGF) antagonist and / or a therapeutic agent for treating OA to the subject if the subject's osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score.

52. The method according to claim 51, wherein the NGF antagonist comprises an antibody, a bispecific antibody, a polypeptide, an antisense nucleic acid molecule, an siRNA molecule, or a small molecule.

53. The method according to claim 52, wherein the antibody comprises facinumab, tanezumab, MEDI7352, or fluranumab.

54. The method according to claim 53, wherein the antibody comprises facinumab.

55. The method according to claim 52, wherein the low molecular weight includes K252a, ALE-0540, PQC-083, PD-90780, LM11A-31 dihydrochloride, Y1036, GZ389988A, or Ro 08-2750.

56. The method according to any one of claims 44 to 50, further comprising administering a nonsteroidal anti-inflammatory drug (NSAID) and / or a therapeutic agent for treating OA to the subject if the subject's osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score.

57. The method according to claim 56, wherein the NSAID comprises ibuprofen, naproxen, diclofenac, etodolac, meloxicam, oxaprozin, celecoxib, piroxicam, indomethacin, or sulindac, or any combination thereof.

58. The method according to any one of claims 44 to 50, further comprising administering an opioid and / or therapeutic agent for treating OA to the subject if the subject's osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score.

59. The method according to claim 58, wherein the opioid includes codeine, hydrocodone, oxycodone, or tramadol, or any combination thereof.

60. The method according to any one of claims 44 to 50, further comprising administering to the subject a NaV1.8, NaV1.7 inhibitor, and / or a therapeutic agent for treating OA, if the subject's osteoarthritis proteomics risk score is less than or equal to the threshold osteoarthritis proteomics risk score.

Images